US8138172B2

US8138172B2 - 8-oxoadenine derivatives acting as modulators of TLR7

Info

Publication number: US8138172B2
Application number: US12/305,801
Authority: US
Inventors: Anthony Cook; Tom McInally; Stephen Thom; Hiroki Wada
Original assignee: Sumitomo Dainippon Pharma Co Ltd; AstraZeneca AB
Current assignee: Sumitomo Pharma Co Ltd; AstraZeneca AB
Priority date: 2006-07-05
Filing date: 2007-07-03
Publication date: 2012-03-20
Also published as: EP2041135A1; JP2009542645A; EP2041135A4; WO2008004948A1; US20100240623A1

Abstract

The present invention provides 8-oxoadenine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The 8-oxoadenine derivatives act as modulators of Toll-like Receptor (TLR) 7 and thus may be used in the treatment of asthma, hepatitis, allergic diseases, viral and bacterial infection as well as cancer.

Description

RELATED APPLICATIONS

The present application is a U.S. National Phase Application of International Application No. PCT/SE2007/000651, filed Jul. 3, 2007, which claims the benefit of U.S. Provisional Application No. 60/818,554, filed Jul. 5, 2006, all of which are hereby incorporated by reference in their entirety.

NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT

The subject matter claimed in this application was made as a result of activities undertaken within the scope of a joint research agreement dated Dec. 19, 2003, between AstraZeneca AB and Sumitomo Pharmaceuticals Co., Ltd. All of the rights and obligations of Sumitomo Pharmaceuticals Co., Ltd. as defined in the joint research agreement between AstraZeneca AB and Sumitomo Pharmaceuticals Co., Ltd. were assumed by Dainippon Sumitomo Pharma Co., Ltd., a company created by the merger of Dainippon Pharmaceuticals Co., Ltd. and Sumitomo Pharmaceuticals Co., Ltd. effective Oct. 3, 2005.

The present invention relates to adenine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The immune system is comprised of innate and acquired immunity, both of which work cooperatively to protect the host from microbial infections. It has been shown that innate immunity can recognize conserved pathogen-associated molecular patterns through toll-like receptors (TLRs) expressed on the cell surface of immune cells. Recognition of invading pathogens then triggers cytokine production (including interferon alpha(IFNα)) and upregulation of co-stimulatory molecules on phagocytes, leading to modulation of T cell function. Thus, innate immunity is closely linked to acquired immunity and can influence the development and regulation of an acquired response.

TLRs are a family of type I transmembrane receptors characterized by an NH₂-terminal extracellular leucine-rich repeat domain (LRR) and a COOH-terminal intracellular tail containing a conserved region called the Toll/IL-1 receptor (TIR) homology domain. The extracellular domain contains a varying number of LRR, which are thought to be involved in ligand binding. Eleven TLRs have been described to date in humans and mice. They differ from each other in ligand specificities, expression patterns, and in the target genes they can induce.

Ligands which act via TLRs (also known as immune response modifiers (IRMS)) have been developed, for example, the imidazoquinoline derivatives described in U.S. Pat. No. 4,689,338 which include the product Imiquimod for treating genital warts, and the adenine derivatives described in WO 98/01448 and WO 99/28321.

This patent application describes a class of 9-substituted-8-oxoadenine compounds having immuno-modulating properties which act via TLR7 that are useful in the treatment of viral or allergic diseases and cancers.

In accordance with the present invention, there is therefore provided a compound of formula (I)

wherein

- R¹represents hydrogen, hydroxyl, or a C₁-C₆alkoxy, C₂-C₅alkoxycarbonyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₆-C₁₀aryl, C₅-C₁₀heteroaryl or C₃-C₈cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, a C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₅alkoxycarbonyl, amino (NH₂), (mono)-C₁-C₆alkylamino and (di)-C₁-C₆alkylamino group;
- Y¹represents a single bond or C₁-C₆alkylene;
- X¹represents a single bond, an oxygen, sulphur atom, sulphonyl (SO₂) or NR³;
- Z¹represents a C₂-C₆alkylene or C₃-C₈cycloalkylene group, each group being optionally substituted by at least one hydroxyl;
- X²represents NR⁴;
- Y²represents a single bond or C₁-C₆alkylene;
- Y³represents a single bond or C₁-C₆alkylene;
- n is an integer 0, 1 or 2;
- R represents halogen or a C₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆hydroxyalkoxy, C₁-C₆haloalkoxy, amino (NH₂), (mono)-C₁-C₆alkylamino, (di)-C₁-C₆alkylamino group or a C₃-C₈saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₂-C₅alkylcarbonyl and C₂-C₅alkoxycarbonyl;
- R²represents hydrogen or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C₁-C₆alkoxy, C₂-C₁₀acyloxy, amino (NH₂), (mono)-C₁-C₆alkylamino, (di)-C₁-C₆alkylamino group and a C₃-C₈saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring in turn being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₂-C₅alkylcarbonyl and C₂-C₅alkoxycarbonyl group;
- R³represents hydrogen or C₁-C₆alkyl;
- R⁴represents CO₂R⁵, SO₂R⁵, COR⁵, SO₂NR⁶R⁷and CONR⁶R⁷;
- R⁵independently represents
(i) a 3- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms comprising ring group NR⁸, S(O)_mor oxygen, each ring may being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C₁-C₆alkyl and C₁-C₆alkoxy group, or
(ii) a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, C₁-C₆alkyl, C₁-C₃haloalkyl, carboxyl, S(O)_mR⁹, OR¹⁰, CO₂R¹⁰, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹, NR¹⁰COR⁹, or
(iii) a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈, cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, CN, C₃-C₈cycloalkyl, S(O)_pR¹², OR¹³, COR¹³, CO₂R¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR¹³R¹⁴, NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², NR¹³SO₂R¹²or a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group or a heterocyclic ring, the latter three groups may be optionally substituted by one or more substituents independently selected from C₁-C₆alkyl (optionally substituted by hydroxy, C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, amino, C₁-C₆alkylamino, di-C₁-C₆alkylamino, amido, C₁-C₆alkylamido, di-C₁-C₆alkylamido, —OCH₂CH₂OH, pyrrolidinyl, pyrrolidinylcarbonyl, furanyl, piperidyl, methylpiperidyl or phenyl), C₁-C₆alkenyl (optionally substituted by phenyl), halogen, hydroxy, cyano, carboxy, amino, C₁-C₆alkylamino, di-C₁-C₆alkylamino, amido, C₁-C₆alkylamido, di-C₁-C₆alkylamido, C₁-C₆alkoxycarbonyl, C₁-C₆alkylsulphonyl, C₁-C₆alkylcarbonylamino, C₁-C₆alkylcarbonylmethylamino, phenyl (optionally substituted by hydroxy, fluoro or methyl), pyrrolidinyl, pyridyl, piperidinyl, benzothiazolyl or pyrimidinyl;
- R⁶represents hydrogen or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl group or heterocyclic ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, OR¹⁵, S(O)_qR¹⁵, CO₂R¹⁶, COR¹⁶, NR¹⁶R¹⁷, CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶CO₂R¹⁵, SO₂NR¹⁶R¹⁷, NR¹⁶SO₂R¹⁵, or a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group or heterocyclic ring, the latter three groups being optionally substituted by one or more substituents independently selected from, C₁-C₆alkyl, C₃-C₈cycloalkyl, halogen, S(O)_qR¹⁵, CO₂R¹⁶, COR¹⁶, hydroxy or cyano; and
- R⁷represents hydrogen, a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₈cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, C₃-C₈cycloalkyl, a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group, carboxy, cyano, OR¹⁵, hydroxy or NR¹⁸R¹⁹, or
- R⁶and R⁷together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)_mor oxygen. The heterocyclic ring, may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, carboxyl, cyano, OR²⁰, NR²¹R²², S(O)_qR²³, COR²⁴, CO₂R²⁴, NR²⁴R²⁵, CONR²⁴R²⁵, NR²⁴COR²⁵, NR²⁴CO₂R²³, SO₂NR²⁴R²⁵, NR²⁴SO₂R²³, C₆-C₁₀aryl , C₅-C₁₀heteroaryl group, heterocyclic ring, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group, the latter seven groups being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, OR²⁰, S(O)_qR²³, COR²⁴, CO₂R²⁴, NR²⁴R²⁵, CONR²⁴R²⁵, NR²⁴CO₂R²³, NR²⁴COR²⁵, SO₂NR²⁴R²⁵, NR²⁴SO₂R²³, a heterocyclic ring or a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group, the latter three groups being optionally substituted by one or more substituents independently selected from C₁-C₆alkyl, halogen, hydroxy or cyano;
- R⁸represents hydrogen, CO₂R²⁶, COR²⁶, SO₂R²⁶, C₁-C₆alkyl or C₃-C₆cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, and NR²⁷R²⁸;
- R¹⁰, R¹¹, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²⁶, R²⁷, R²⁸, R²⁹or R³⁰each independently represents hydrogen, and a C₁-C₆alkyl or C₃-C₆cycloalkyl group;
- R²⁴and R²⁵each independently represents hydrogen, and a C₁-C₆alkyl or C₃-C₆cycloalkyl group; or
- R²⁴and R²⁵together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)_mor oxygen;
- R⁹, R¹², R¹⁵and R²³represent C₁-C₆alkyl or C₃-C₆cycloalkyl;
- R¹³and R¹⁴are defined as for R⁶and R⁷respectively;
- R²⁰represents a C₁-C₆alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl or OR²³;
- m, p, q and r each independently represent an integer 0, 1 or 2; and
- A represents a C₆-C₁₀aryl or C₅-C₁₂heteroaryl group;

or a pharmaceutically acceptable salt thereof.

In the context of the present specification, unless otherwise stated, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. Examples of C₁-C₆alkyl groups/moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Similarly, an alkylene group/moiety may be linear or branched. Examples of C₁-C₆alkylene groups/moieties include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene and 1-, 2- or 3-ethylpropylene. A C₁-C₆haloalkyl or C₁-C₆haloalkoxy substituent group/moiety will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl. The alkyl groups in a di-C₁-C₆alkylamino group/moiety may be the same as, or different from, one another. A C₁-C₆hydroxyalkyl or C₁-C₆hydroxyalkoxy substituent group/moiety will comprise at least one hydroxyl group, e.g. one, two or three hydroxyl groups. An aryl or heteroaryl substituent group/moiety may be monocyclic or polycyclic (e.g. bicyclic or tricyclic) in which the two or more rings are fused. A heteroaryl group/moiety will comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of aryl and heteroaryl groups/moieties include phenyl, 1-naphthyl, 2-naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, isoindolyl, quinolyl, isoquinolyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl and oxazolyl. A heterocyclic ring is defined as a saturated or partially saturated 3-8 membered ring containing at least one hetero atom or group selected from nitrogen, sulphur, SO, SO₂or oxygen. The ring may be fused with a C₆-C₁₀aryl or C₅-C₁₂heteroaryl group. Examples include morpholine, azetidine, pyrrolidine, piperidine, piperazine, 3-pyrroline, isoindoline, tetrahydroquinoline and thiomorpholine.

A C₂-C₁₀acyloxy group/moiety is exemplified by a C₂-C₅alkylcarbonyloxy group, a C₂-C₅alkenylcarbonyloxy group, a C₂-C₅alkynylcarbonyloxy group, a C₆-C₉arylcarbonyloxy group or a C₅-C₉heteroarylcarbonyloxy group, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C₁-C₃alkoxy or phenyl providing that the total number of carbon atoms in the acyloxy group does not exceed 10.

Preferably X¹represents oxygen.
Preferably Y¹represents C₁-C₆alkylene and R¹represents hydrogen
Preferably Z¹represents C₂-C₆alkylene, more preferably (CH₂)₃.
Preferably Y²represents C₁-C₆alkylene, more preferably a CH₂group.
Preferably A represents a C₆-C₁₀aryl, more preferably phenyl.
Preferably Y³represents C₁-C₆alkylene, more preferably CH₂.
Preferably R²represents C₁-C₆alkyl more preferably methyl.
Preferably R⁴represents SO₂R⁵or COR⁵.

Examples of compounds of the invention include:

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(4-methylpiperazin-1-yl)acetyl]amino}methyl)phenyl]acetate,
Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethylglycyl)amino]methyl}phenyl)acetate,
Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][4-(dimethylamino)butanoyl]amino}methyl)phenyl]acetate,
Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethyl-β-alanyl)amino]methyl}phenyl)acetate,
Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N,N-bis(2-hydroxyethyl)glycyl]amino}methyl)phenyl]acetate,
Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate,
Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(methylsulfonyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](glycyl)amino]methyl}phenyl)acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylthio)acetyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfinyl)acetyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfonyl)acetyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylthio)propanoyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylsulfonyl)propanoyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N-(methylsulfonyl)glycyl]amino}methyl)phenyl]acetate,
tert-Butyl 4-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoate,
4-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoic acid,
Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-3-oxopropanoate,
Methyl[3-({acetyl[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate,
Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](methylsulfonyl)amino]methyl}phenyl)acetate,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)[2R]-propyl]-(pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S,4R](4-hydroxy-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S]-(1-methyl-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(3-piperazin-1-yl-propionyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[3-(1-piperidyl)propyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[3-(diethylcarbamoyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Ethyl 4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]piperazine-1-carboxylate,
2-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(2-cyanoethyl)amino]acetic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(benzyl-(2-dimethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-carbamoyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-hydroxypyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
tert-Butyl (2S)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2-cyanoethyl-(oxolan-2-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(pyridin-4-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2-pyridin-4-ylethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrrolidin-1-yl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,6-dihydro-2H-pyridin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(cyclohexyl-(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(hydroxymethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-aminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-hydroxyethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[methyl-(1-methyl-4-piperidyl)amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzyl-4-hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-cinnamylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3-dimethylaminopropyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(dimethylcarbamoylmethyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-1,4-diazepan-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-morpholin-4-ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-hydroxyphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[[2-[3-(acetyl-methyl-amino)pyrrolidin-1-yl]acetyl]-[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3S)-3-dimethylaminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-4-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-dimethylaminopropyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-propan-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(dimethylcarbamoylmethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2-hydroxy-2-phenyl-ethyl)-methyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(aminomethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2-methylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-thiomorpholin-4-ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1,3-dihydroisoindol-2-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-piperazin-1-ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(1-piperidyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(4-fluorophenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2,5-dihydropyrrol-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzothiazol-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(ethoxycarbonylmethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-dimethylaminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-methylphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylsulfonylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
(2S,4R)-1-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]-4-hydroxy-pyrrolidine-2-carboxylic acid,
(2S)-2-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-methyl-amino]-3-phenyl-propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(1,1-dioxothiolan-3-yl)amino]propanoic acid,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-cyclohexyl-amino]propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(2-ethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(3-ethylaminopropyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,4-dihydro-1H-isoquinolin-2-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[(1-methyl-4-piperidyl)methyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-prop-2-ynyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(1-methyl-4-piperidyl)-phenethyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(oxolan-2-ylmethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-aminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
tert-Butyl (2R)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrimidin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-pyrrolidin-1-ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

and pharmaceutically acceptable salts thereof.

The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises,

(a) when R⁴represents COR⁵, reacting a compound of formula (II)

wherein n, A, Y¹, Y², Y³, X¹, Z¹, R, R¹and R²are as defined in formula (I), with a compound of formula (III), wherein R⁵is as defined in formula (I), using an appropriate coupling reagent (for example, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)), in the presence of a base such as diisopropyl ethylamine, triethylamine or pyridine in an organic solvent (for example dimethylformamide, dichloromethane or acetonitrile) at a temperature in the range, for example, from 0 to 150° C. [alternatively, the acid (III) may be activated by formation of an acid halide using a halogenating reagent such as oxalyl chloride or thionyl chloride; the acid chloride may then be reacted with a compound of formula (II) in the presense of a base such as diisopropyl ethylamine, triethylamine or pyridine in an organic solvent (for example dimethylformamide, dichloromethane or acetonitrile) at a temperature in the range, for example, from 0 to 150° C.];

(b) when R⁴represents COR⁵and R⁵represents C₁-C₆alkyl substituted by NR¹³R¹⁴, reacting a compound of formula (IV)

wherein L²represents a leaving group such as a halogen, mesylate or triflate, t is an integer from 1 to 6, and n, A, Y¹, Y², Y³, X¹, Z¹, R, R¹and R²are as defined in formula (I), with a compound of formula

wherein R¹³and R¹⁴are as defined in formula (I) [the reaction may be carried out in the presense of a base (for example diisopropyl ethylamine, triethylamine or pyridine) in an organic solvent such as dimethylformamide, dimethylsulphoxide or acetonitrile at a temperature, for example, in the range from 0 to 150° C.];

(c) when R⁴represents a group SO₂R⁵, reacting a compound of formula (II) as defined in (a) above with a compound of formula (VI), L³-S(O)₂—R⁵, wherein L³represents a leaving group (e.g. halogen) and R⁵is as defined in formula (I), in the presence of a base;
(d) when R⁴represents a group CO₂R⁵, reacting a compound of formula (II) as defined in (a) above with a compound of formula (VII), L⁴-C(O)—OR⁵, wherein L⁴represents a leaving group (e.g. halogen) and R⁵is as defined in formula (I), in the presence of a base;
(e) when R⁴represents a group SO₂NR⁶R⁷, reacting a compound of formula (II) as defined in (a) above with a compound of formula (VIII), L⁵-S(O)₂—NR⁶R⁷, wherein L⁵represents a leaving group (e.g. halogen) and R⁶and R⁷are as defined in formula (I), in the presence of a base;

or

(f) when R⁴represents a group CONR⁶R⁷, reacting a compound of formula (II) as defined in (a) above with a compound of formula (IX), L⁶-C(O)—NR⁶R⁷, wherein L⁶represents a leaving group (e.g. halogen) and R⁶and R⁷are as defined in formula (I), in the presence of a base;

and optionally thereafter carrying out one or more of the following procedures:

- converting a compound of formula (I) into another compound of formula (I),
- removing any protecting groups,
- forming a pharmaceutically acceptable salt.

In each of processes (c), (d), (e) and (f) above, the reaction is conveniently carried out in an organic solvent such as dimethylformamide, dichloromethane or acetonitrile at a temperature in the range from 0° C. to 150° C. Suitable bases include diisopropyl ethylamine, triethylamine and pyridine.

A compound of formula (IV) may be prepared by reacting a compound of formula (II) with a compound of formula (X)

wherein L²and t are as defined in formula (IV). The reaction may be carried out using similar conditions to couple compounds of formulae (II) and (III).

A compound of formula (II) may be obtained by the treatment of a compound of formula (XI)

wherein n, A, Y¹, Y², Y³, X¹, Z¹, R, R¹and R²are as defined in formula (I) with an acid. The reaction may be carried out in an organic solvent such as methanol, tetrahydrofuran or dioxane using either an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid.

A compound of formula (XI) may be obtained by the treatment of a compound of formula (XII)

wherein Z¹, X¹, Y¹and R¹are as defined in formula (I) with a compound of formula (XIII), wherein Y⁴represents a bond or a C₁-C₅alkylene group and n, A, Y³, R and R²are as defined in formula (I). The reaction may be carried out in the presense of a suitable reducing agent (for example sodium triacetoxyborohydride or sodium borohydride), in an organic solvent such as 1-methyl-2-pyrrolidinone, 1,2-dichloroethane, tetrahydrofuran or methanol at a temperature, for example, in the range from 0 to 150° C.

A compound of formula (XII) above may be obtained by treatment of a compound of formula

wherein Z¹, X¹, Y¹and R¹are as defined in formula (I) and PG₁represents a protecting group, e.g. phthalimide or Fmoc, which may be deprotected using hydrazine in ethanol or an organic base such as piperidine.

A compound of formula (XIV) may be prepared by reacting a compound of formula (XV)

wherein X¹, Y¹and R¹are as defined in formula (I), with a compound of formula (XVI), L⁷-Z¹—NH—PG₁, wherein L⁷represents a leaving group such as a halogen, mesylate or triflate, and Z¹is as defined in formula (I) and PG₁is as defined above. The reaction may conveniently be carried out in an organic solvent such as dimethylformamide, dimethylsulphoxide or acetonitrile in the presense of a base such as an alkali metal carbonate (for example sodium carbonate or potassium carbonate) or an alkaline earth metal carbonate (for example calcium carbonate), a metal hydroxide (for example sodium hydroxide or potassium hydroxide) at a temperature, for example, in the range from 0 to 150° C., preferably at room temperature (20° C.).

The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3^rdedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).

The compounds defined in the formula (XV) may be obtained following the procedure described in the patent WO2005/092893.

Compounds of formulae (III), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XIII) and (XVI) are either commercially available, are well known in the literature or may be prepared using known techniques.

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or p-toluenesulphonate.

Compounds of formula (I) is capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators of toll-like receptor (especially TLR7) activity, and thus may be used in the treatment of:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial;
4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
6. other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome and Sazary syndrome;
7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
8. infectious diseases: virus diseases such as genital warts, common warts, plantar warts, respiratory syncytial virus (RSV), hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, candida, aspergillus, cryptococcal meningitis, pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.

Thus, the present invention provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

In particular, the compounds of the invention may be used in the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, respiratory syncytial virus (RSV), bacterial infections and dermatosis.

The invention still further provides a method of treating, or reducing the risk of, an obstructive airways disease or condition (e.g. asthma or COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.

Dry powder formulations and pressurized HFA aerosols of the compounds of the invention (including pharmaceutically acceptable salts) may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 micrometres (μm), and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C₈-C₂₀fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.

For oral administration the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.

The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases COPD, asthma and allergic rhinitis the compounds of the invention may be combined with agents such as tumour necrosis factor alpha (TNF-alpha) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab [Remicade®], CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (such as entanercept [Enbrel®]); non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids (whether administered by topical,oral, intramuscular, intravenous, or intra-articular routes); methotrexate, lefunomide; hydroxychloroquine, d-penicillamine, auranofin or other parenteral or oral gold preparations.

The present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT B4, LTC4, LTD4, and LTE4) selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.

The present invention still further relates to the combination of a compound of the invention and a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the invention and an anticholinergic agent including muscarinic receptor (M1, M2, and M3) antagonists such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of a compound of the invention together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.

The present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-1) mimetic.

The present invention still further relates to the combination of a compound of the invention and a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12.

The present invention still further relates to the combination of a compound of the invention together with modulators of chemokine receptor function such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX3CR1 for the C—X3—C family.

The present invention still further relates to the combination of a compound of the invention together with a cytokine or modulator of cytokine function, including alpha-, beta-, and gamma-interferon; interleukins (IL) including IL1 to 15, and interleukin antagonists or inhibitors, including agents which act on cytokine signalling pathways.

The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (omalizumab).

The present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:

(i) an antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux®, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29) such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)];
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell allergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

The present invention will be further explained by reference to the following illustrative examples.

The following abbreviations are used;


EtOAc	ethyl acetate
DCM	dichloromethane
NMP	N-methylpyrrolidine
NBS	N-bromosuccinimide
DMF	N,N-dimethylformamide
DMSO	dimethylsulfoxide
THF	tetrahydrofuran
TFA	trifluoroacetic acid
K₂CO₃	potassium carbonate
NaHCO₃	sodium hydrogen carbonate
MeCN	acetonitrile
mCPBA	3-chloroperoxybenzoic acid (Aldrich 77% max)
rt	room temperature
h	hours
min	minutes
M	molar
N	normal
MS	mass spectrometry
APCI	atmospheric chemical ionisation method
ESI	electron spray ionisation method
NMR	nuclear magnetic resonance
HCl	hydrochloric acid
BOC	tertiary-butoxycarbonyl
HOBt	1-hydroxybenzotriazole
EDC	1-(3-dimethylamino propyl)-3-ethylcarbodiimide
	hydrochloride
HATU	O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
	hexafluorophosphonate

Unless otherwise stated organic solutions were dried over magnesium sulphate. RPHPLC denotes Reversed Phase Preparative High Performance Liquid Chromatography using Waters® Symmetry® C8, XTerra® or Phenomenex® Gemini™columns using acetonitrile and either aqueous ammonium acetate, ammonia, formic acid or trifluoroacetic acid as buffer where appropriate. Column chromatography was carried out on silica gel. SCX denotes solid phase extraction with a sulfonic acid sorbent whereby a mixture was absorbed on a sulfonic acid sorbent and eluted with an appropriate solvent such as methanol or acetonitrile and then the free base product was eluted with aqueous ammonia/an appropriate solvent such as methanol or acetonitrile.

EXAMPLE 1

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(4-methylpiperazin-1-yl)acetyl]amino}methyl)phenyl]acetate (i) 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolved in 7N-aqueous ammonia in methanol (500 ml) and heated at 100° C. in a sealed flask for 6 h. The reaction mixture was cooled to rt and left overnight. Filtration afforded the subtitle compound. Yield 40 g.

¹H NMR δ (CDCl₃) 8.02 (1H, s), 5.94 (2H, brs), 5.71 (1H, dd), 4.15-4.22 (1H, m), 3.75-3.82 (1H, m), 1.27-2.12 (6H, m).

(ii) 2-Butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

The product from step (i) (40 g) was dissolved in 19% (w/w)-sodium butoxide in butanol (250 ml). The reaction mixture was stirred under reflux for 6 h. The resultant suspension was cooled to rt, diluted with water and extracted with diethyl ether. The combined organic phase was washed with water, dried and concentrated in vacuo. The subtitle compound was crystallized from diethyl ether/isohexane (1/1, 300 ml) and obtained by filtration. Yield 19 g.

¹H NMR

(CDCl₃) 7.87 (1H, s), 5.56-5.68 (3H, m), 4.31-4.35 (2H, t), 4.14-4.17 (1H, m), 3.76-3.80 (1H, m), 1.49-2.08 (10H, m), 0.98 (3H, t).

(iii) 8-Bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-amine

The product from step (ii) (30 g) was dissolved in dry DCM (200 ml). The solution was stirred at rt whilst N-bromosuccinimide (27 g) was added portion wise. The mixture was stirred at rt overnight. 20% (w/v)-Sodium sulfate (200 ml) was added and the separated aqueous phase extracted with DCM. The combined organic phase was washed with saturated NaHCO₃solution and brine. After concentration in vacuo, the residue was dissolved in EtOAc, washed with water, brine and dried. The solution was filtered through silica gel. The filtrate was concentrated in vacuo and dissolved in a mixture of diethyl ether and isohexane (1/1, 200 ml) to give the subtitle compound (26 g). The solvent was removed to give a residue, which was purified by column chromatography (EtOAc/isohexane), which afforded 2.5 g. The solids were combined to give the subtitle compound as a yellow solid. Yield 28.5 g. mp 148-50° C.

¹H NM

δ(CDCl₃) 5.59-5.64 (3H, m), 4.32 (2H, m), 4.17 (1H, m), 3.74 (1H, m), 3.08 (1H, m), 2.13 (1H, d), 1.48-1.83 (8H, m), 0.98 (3H, t).

(iv) 2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-amine

Sodium (3.7 g) was added to absolute methanol (400 ml) under a nitrogen atmosphere. To this solution was added the product (28.5 g) from step (iii) and the mixture was stirred at 65° C. for 9 h. The mixture was concentrated in vacuo and 500 ml of water added. The aqueous phase was extracted with EtOAc and washed with brine and dried. The subtitle compound was obtained after crystallisation from diethyl ether. Yield 14.2 g.

¹H NMR

(CDCl₃) 5.51(1H, dd), 5.28 (2H, brs), 4.29 (2H, t), 4.11-4.14 (4H, m), 3.70 (1H, m), 2.76-2.80 (1H, m), 2.05 (1H, d), 1.47-1.81 (8H, m), 0.97 (3H, t).

(v) 2-Butoxy-8-methoxy-9H-purin-6-amine, TFA Salt

The product from step (iv) (24 g) was dissolved in absolute methanol (300 ml) and 30 ml of TFA was added. The reaction mixture was stirred at rt for 3 days and concentrated in vacuo. The subtitle compound was obtained as a white crystalline solid after trituration with methanol/EtOAc. Yield 21 g.

¹H NMR δ (CD₃OD) 4.48 (2H, t), 4.15 (3H, s), 1.80 (2H, quintet), 1.50 (2H, sextet), 0.99 (3H, t).

(vi) 2-[3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]-1H-isoindole-1,3(2H)-dione

The product from step (v) (15 g) was dissolved in dry DMF (200 ml) and 18 g of K₂CO₃added. After the suspension was stirred at rt for 15 min, 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (14 g) was added the the suspension vigorously stirred at rt for 10 h. The reaction mixture was extracted with EtOAc, washed with water and brine and dried. The subtitle compound was obtained after crystallisation from EtOAc/diethyl ether. Yield 16 g.

¹H NMR δ (DMSO-d₆) 7.83 (4H, m), 6.73 (2H, brs), 4.06 (2H, t,), 4.01 (3H, s), 3.89 (2H, t), 3.58 (2H, t), 2.07-2.14 (2H, m), 1.55-1.62 (2H, m), 1.31-1.40 (2H, m), 0.90 (3H, t).

(vii) 9-(3-Aminopropyl)-2-butoxy-8-methoxy-9H-purin-6-amine

The product from step (vi) (1 g) was dissolved in ethanol (10 ml) and hydrazine monohydrate (1 ml) was added and stirred at ambient temperature for 10 h. The resultant was concentrated under reduced pressure and the residue suspended in DCM (10 ml) and stirred for 1 h. The suspension was filtered, washed with DCM. The solution was washed with water and dried. The solution was concentrated under reduced pressure to give the subtitled compound. Yield 700 mg.

¹H NMR δ (DMSO-d₆) 6.77 (2H, brs), 4.16 (2H, t), 4.05 (3H, s), 3.89 (2H, t), 2.46-2.52 (2H, m), 1.61-1.76 (4H, m), 1.35-1.45 (2H, m), 0.92 (3H, t).

(viii) [4-({[3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetic acid

The product from step (vii) (9.7 g) and (4-formylphenyl)acetic acid (5.4 g) were dissolved in THF (100 ml) and stirred at rt for 4 h. Sodium borohydride (1.9 g) and 5 drops of methanol was added and stirred at a rt overnight. The mixture was quenched with water and concentrated under reduced pressure. Water was added and washed with diethyl ether. 0.1N—HCl was added to acidify the solution to pH 6. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 13 g.

¹H NMR δ (DMSO-d₆) 7.14-7.22 (4H, m), 6.75 (2H, brs), 4.12 (2H, t), 4.03 (3H, s), 3.88 (2H, t), 3.62 (2H, s), 3.38 (2H, s), 1.34-2.47 (8H, m), 0.91 (3H, t).

(ix) Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate

The product from step (viii) (13 g) was dissolved in methanol (100 ml) and 4N—HCl in dioxane (10 ml) added. The reaction mixture was stirred at rt for 24 h. The resultant was concentrated under reduced pressure and aqueous NaHCO₃added to pH 8. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 11 g.

¹H NMR δ (DMSO-d₆) 7.15-7.25 (4H, m), 6.35 (2H, brs6), 4.12 (2H, t), 3.71 (2H, t), 3.62 (3H, s), 3.62 (2H, s), 3.60 (2H, s), 2.47 (2H, m), 1.34-1.80 (6H, m), 0.90 (3H, t).

(x) Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(4-methylpiperazin-1-yl)acetyl]amino}methyl)phenyl]acetate

The product from step (ix) (200 mg) was suspended in MeCN. Chloroacetyl chloride (0.02 ml) added and the mixture stirred at rt for 4 h. The mixture was concentrated under reduced pressure, piperazine (0.02 ml) in DMSO (1 ml) was added and the mixture heated at 60° C. for 24 h. The mixture was purified by RPHPLC. Yield 80 mg.

¹H NMR δ (DMSO-d₆) 10.02 (1H, brs), 7.10-7.20 (4H, m), 6.30 (2H, brs), 4.52 (2H, m), 4.15 (3H, t), 3.60-3.66 (7H, m), 3.27 (4H, m), 2.98 (4H, m), 2.73 (4H, m), 2.61 (3H, s), 1.33-1.94 (6H, m), 0.92 (3H, t).

MS: APCI (+ve): 583 (M+H).

EXAMPLE 2

Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethylglycyl)amino]methyl}phenyl)acetate

The product of example 1, step (ix) (200 mg) was suspended in MeCN. N,N-dimethylglycyl chloride hydrochloride (110 mg) and triethylamine (0.19 ml) were added and the mixture stirred at rt for 10 h. The mixture was purified by RPHPLC. Yield 100 mg.

¹H NMR δ (DMSO-d₆) 7.07-7.22 (4H, m), 6.43 (2H, brs), 4.55 (2H, s), 4.13 (2H, t), 3.63-3.69 (4H, m), 3.60 (3H, s), 3.29 (2H, m), 3.01 (2H, s), 2.14 (2H, s), 1.31-1.97 (6H, m), 0.90 (3H, t).

MS: APCI (+ve): 528 (M+H).

EXAMPLE 3

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate

The title compound was prepared by the method of example 2 using 1-methylpiperidine-4-carbonyl chloride hydrochloride, yield 50 mg.

¹H NMR δ (DMSO-d₆) 7.04-7.24 (4H, m), 6.45 (2H, brs), 4.51 (2H, s), 4.13 (2H, t), 3.60-3.65 (7H, m), 3.17-3.31 (4H, m), 2.66 (2H, s), 2.07 (3H, s), 1.35-2.02 (11H, m), 0.90 (3H, t).

MS: APCI (+ve): 568 (M+H).

EXAMPLE 4

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][4-(dimethylamino)butanoyl]amino}methyl)phenyl]acetate

The title compound was prepared by the method of example 2 using 4-(dimethylamino)butanoyl chloride hydrochloride, yield 30 mg.

¹H NMR δ (DMSO-d₆) 7.05-7.24 (4H, m), 6.40 (2H, brs), 4.55 (2H, s), 4.12 (2H, t), 3.39-3.65 (7H, m), 3.23 (2H, m), 2.10-2.27 (4H, m), 2.04 (6H, s), 1.33-1.93 (8H, m), 0.91 (3H, t).

MS: APCI (+ve): 556 (M+H).

EXAMPLE 5

Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethyl-β-alanyl)amino]methyl}phenyl)acetate

The title compound was prepared by the method of example 2 using N,N-dimethyl-β-alanyl chloride hydrochloride, yield 55 mg.

¹H NMR δ (DMSO-d₆) 7.06-7.24 (4H, m), 6.40 (2H, brs), 4.51 (2H, s), 4.12 (2H, t), 3.62-3.69 (7H, m), 3.60 (3H, s), 3.23 (2H, m), 2.40 (4H, m), 2.05 (6H, s), 1.34-1.93 (6H, m), 0.90 (3H, t).

MS: APCI (+ve): 542 (M+H).

EXAMPLE 6

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N,N-bis(2-hydroxyethyl)glycyl]amino}methyl)phenyl]acetate

The title compound was prepared by the method of example 1 using 2,2′-iminodiethanol, yield 30 mg.

¹H NMR δ (DMSO-d₆) 7.09-7.20 (4H, m), 4.59 (2H, brs), 4.22 (2H, m), 3.78 (2H, t), 3.64 (3H, s), 3.45-3.61 (10H, m), 2.71 (4H, m), 1.44-2.10 (6H, m), 0.95 (3H, t).

MS: APCI (+ve): 588 (M+H).

EXAMPLE 7

Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate

The title compound was prepared by the method of example 1 using 2-piperazin-1-ylethanol, yield 52 mg.

¹H NMR δ (DMSO-d₆) 9.87 (1H, brs), 7.06-7.21 (4H, m), 6.41 (2H, brs), 4.55 (2H, s), 4.22 (2H, m), 3.63-3.69 (4H, m), 3.60 (3H, s), 3.20 (2H, m), 3.04 (2H, s), 1.36-2.37 (18H, m), 0.90 (3H, t).

MS: APCI (+ve): 613 (M+H).

EXAMPLE 8

Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(methylsulfonyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate

The title compound was prepared by the method of example 1 using 1-(methylsulfonyl)piperazine, yield 25 mg.

¹H NMR δ (DMSO-d₆) 7.07-7.24 (4H, m), 6.44 (2H, brs), 4.54 (2H, s), 4.12 (2H, m), 3.63-3.67 (4H, m), 3.60 (3H, s), 3.15 (2H, s), 3.03 (4H, m), 2.83 (2H, s), 2.40 (4H, m), 1.33-1.90 (6H, m), 0.90 (3H, t).

MS: APCI (+ve): 647 (M+H).

EXAMPLE 9

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate (i) tert-Butyl[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]carbamate

The product from example 1 step (v) (1.5 g), 1.4 g of K₂CO₃and tert-butyl (3-bromopropyl)carbamate (1 g) were heated at 50° C. in DMF (10 ml) for 3 h. The reaction mixture was cooled to rt, extracted with EtOAc, washed with water and dried. The solvent was removed to give a residue, which was purified by column chromatography (methanol/DCM), which afforded the subtitle compound. Yield 1.1 g.

¹H NMR δ (DMSO-d₆) 6.82 (1H, t), 6.77 (2H, s), 4.17 (2H, t,), 4.04 (3H, s), 3.83 (2H, t), 2.90 (2H, m), 1.79 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 1.37 (9H, s), 0.92 (3H, t).

(ii) 6-Amino-9-(3-aminopropyl)-2-butoxy-7,9-dihydro-8H-purin-8-one

The product from step (i) (1.1 g) was dissolved in methanol/DCM (1/1, 40 ml). 4N—HCl in dioxane (10 ml) was added and the mixture stirred at rt for 20 h. The resultant was concentrated under reduced pressure, which afforded the subtitle compound. Yield 0.9 g.

¹H NMR δ (DMSO-d₆) 10.71 (1H, brs), 7.88 (2H, brs), 4.22 (2H, t,), 3.75 (2H, t), 2.77 (2H, m), 1.96 (2H, m), 1.36-1.70 (4H, m), 0.92 (3H, t).

(iii) Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate

The product from step (ii) (3.1 g) and methyl(3-formylphenyl)acetate (1.6 g) were dissolved in NMP (30 ml) and stirred for 15 min. Sodium triacetoxyborohydride (3.7 g) was added and the mixture stirred at rt for 20 h. After addition of methanol (1 ml), the mixture was purified by SCX, which afforded the subtitle compound. Yield 3.1 g.

¹H NMR δ (DMSO-d₆) 7.27-7.21 (3H, m), 7.13 (1H, m), 6.46 (2H, brs), 4.12 (2H, t), 3.73 (2H, t), 3.70 (2H, s), 3.64 (2H, s), 3.61 (3H, s), 2.54 (2H, t), 1.82 (2H, m), 1.62 (2H, m), 1.37 (2H, m), 0.90 (3H, t).

(iv) Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate

The product from step (iii) (0.1 g), diisopropyl ethylamine (0.1 ml) and 1-methylpiperidine-4-carboxylic acid hydrochloride (45 mg) were dissolved in NMP (3 ml) then HATU (130 mg) added to the mixture. The mixture was stirred at rt for 5 h then purified by SCX and RPHPLC, which afforded the title compound. Yield 70 mg.

¹H NMR δ (DMSO-d₆) 7.23 (1H, t), 7.12 (1H, d), 7.03 (1H, s), 7.02 d), 6.15 (2H, brs), 4.50 (2H, s), 4.16 (2H, t), 3.65 (2H, t), 3.61 (2H, s), 3.60 (3H, s), 3.25 (2H, t), 2.68 (2H, m), 2.10 (3H, s), 1.86-1.96 (2H, m), 1.63 (5H, m), 1.42 (4H, m), 0.91 (3H, t).

MS: APCI (+ve): 568 (M+1).

EXAMPLE 10

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate

The title compound was prepared by the method of example 10 using N-(tert-butoxycarbonyl)glycine, yield 160 mg.

¹H NMR δ (DMSO-d₆) 9.69 (1H, s), 7.27 (1H, m), 7.17 (1H, m), 7.09 (2H, m), 6.35-6.25 (1H, m), 6.14 (2H, brs), 4.54 (2H, s), 4.20 (2H, t), 3.83 (2H, d), 3.69 (2H, t), 3.65 (2H, s), 3.64 (3H, s), 3.31 (2H, t), 1.95 (2H, m), 1.68 (2H, m), 1.43 (2H, m), 1.40 (9H, s), 0.95 (3H, t).

MS: APCI (+ve): 600 (M+1).

EXAMPLE 11

Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](glycyl)amino]methyl}phenyl)acetate

The product from example 10 (150 mg) was dissolved in methanol (2 ml) and 4N HCl in dioxane added. The mixture was stirred at rt for 3 h and purified by RPHPLC, which afforded the title compound. Yield 20 mg.

¹H NMR δ (DMSO-d₆) 7.24 (1H, m), 7.13 (1H, m), 7.05 (2H, m), 6.13 (2H, brs), 4.50 (2H, s), 4.17 (2H, s), 3.66 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.33 (2H, s), 3.24-3.31 (2H, m), 1.92 (2H, m), 1.65 (2H, m), 1.40 (2H, m), 0.93 (3H, t).

MS: APCI (+ve): 500 (M+1).

EXAMPLE 12

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylthio)acetyl]amino}methyl)phenyl]acetate

The title compound was prepared by the method of example 10 using (methylthio)acetic acid, yield 170 mg.

¹H NMR δ (DMSO-d₆) 7.24 (1H, m), 7.14 (1H, m), 7.07 (2H, m), 6.13 (2H, brs), 4.48-4.60 (2H, m), 4.17 (2H, t), 3.67 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.33 (2H, s), 3.30 (2H, t), 2.09 (3H, s), 1.90-2.02 (2H, m), 1.65 (2H, m), 1.40 (2H, m), 0.92 (3H, t).

MS: APCI (+ve): 531 (M+1).

EXAMPLE 13

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfinyl)acetyl]amino}methyl)phenyl]acetate

The product from example 12 (150 mg) was dissolved in DCM (10 ml) and methanol (2 ml) and mCPBA (0.1 g) added. The mixture was stirred at rt for 3 h then purified by RPHPLC, which afforded the title compound. Yield 50 mg.

¹H NMR δ (DMSO-d₅) 7.00-7.31 (4H, m), 6.14 (2H, brs), 4.46-4.70 (2H, m), 4.17 (2H, t), 3.92 (2H, s), 3.67 (2H, s), 3.61 (3H, s), 3.02 (4H, m), 2.62 (3H, s), 1.85-2.11 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 0.93 (3H, t).

MS: APCI (+ve): 547 (M+1).

EXAMPLE 14

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfonyl)acetyl]amino}methyl)phenyl]acetate

The product from example 12 (150 mg) was dissolved in DCM (10 ml) and methanol (2 ml) and mCPBA (0.1 g) added. The mixture was stirred at rt for 3 h then purified by RPHPLC, which afforded the title compound. Yield 40 mg.

¹H NMR δ (DMSO-d₆) 7.05-7.39 (4H, m), 6.15 (2H, brs), 4.60 (2H, m), 4.35 (2H, m), 4.17 (2H, t), 3.68 (2H, s), 3.62 (3H, s), 3.11 (3H, s), 3.03 (4H, m), 1.84-2.05 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 1.10 (3H, t).

MS: APCI (+ve): 563 (M+1).

EXAMPLE 15

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylthio)propanoyl]amino}methyl)phenyl]acetate

The title compound was prepared by the method of example 10 using 3-(methylthio)propanoic acid, yield 130 mg.

¹H NMR δ (DMSO-d₆) 7.25 (1H, m), 7.14 (1H, m), 7.07 (2H, m), 6.13 (2H, brs), 4.53 (2H, s), 4.17 (2H, t), 3.67 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.31 (2H, t), 2.68 (2H, m), 2.58 (2H, m), 2.01 (3H, s), 1.99-1.89 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 0.93 (3H, t).

MS: APCI (+ve): 545 (M+1).

EXAMPLE 16

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylsulfonyl)propanoyl]amino}methyl)phenyl]acetate

The title compound was prepared by the method of example 14 using the product from example 15, yield 60 mg.

¹H NMR δ (DMSO-d₆) 7.24 (1H, m), 7.14 (1H, m), 7.06 (2H, m), 6.13 (2H, brs), 4.61-4.50 (2H, m), 4.16 (2H, t), 3.67 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.34 (4H, m), 2.92 (3H, s), 2.80 (2H, t), 1.89-2.00 (2H, m), 1.65 (2H, m), 1.40 (2H, m), 0.92 (3H, t).

MS: APCI (+ve): 577 (M+1).

EXAMPLE 17

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N-(methylsulfonyl)glycyl]amino}methyl)phenyl]acetate

The product from example 11 (50 mg) was dissolved in NMP (1 ml), then pyridine (0.07 ml) and methanesulfonic anhydride (29 mg) added. The mixture was stirred at rt for 20 h then purified by RPHPLC, which afforded the title compound. Yield 15 mg

¹H NMR δ (DMSO-d₆) 7.25 (1H, m), 7.15 (1H, m), 7.07 (2H, m), 6.15 (2H, brs), 4.53 (2H, s), 4.17 (2H, t), 3.91 (2H, s), 3.67 (2H, t), 3.63 (2H, s), 3.62 (3H, s), 3.31 (2H, t), 2.92 (3H, s), 1.89-1.99 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 0.93 (3H, t).

MS: APCI (+ve): 576 (M+1).

EXAMPLE 18

tert-Butyl 4-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoate

The title compound was prepared by the method of example 10 using 4-tert-butoxy-4-oxobutanoic acid, yield 17 mg.

¹H NMR δ (DMSO-d₆) 7.22 (1H, m), 7.12 (1H, m), 7.05 (2H, m), 6.11 (2H, brs), 4.51 (2H, s), 4.16 (2H, t), 3.65 (2H, t), 3.60 (2H, s), 3.60 (3H, s), 3.29 (2H, m), 2.50 (2H, m), 2.42 (2H, m), 1.85-1.98 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 1.36 (9H, s), 0.91 (3H, t).

MS: APCI (+ve): 599 (M+1).

EXAMPLE 19

4-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoic acid

The product from example 18 (140 mg) was dissolved in DCM (1 ml) and TFA (0.2 ml) added. The mixture was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO₃solution and dried. The mixture was purified by RPHPLC, which afforded the title compound. Yield 80 mg.

¹H NMR δ (DMSO-d₆) 9.66 (1H, s), 7.22 (1H, m), 7.12 (1H, m), 7.05 (2H, m), 4.52 (2H, brs), 4.16 (2H, t), 3.65 (2H, t), 3.61 (2H, s), 3.60 (3H, s), 3.29 (2H, m), 2.54 (2H, m), 2.46 (2H, m), 1.85-1.98 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 0.91 (3H, t).

MS: APCI (+ve): 543 (M+1).

EXAMPLE 20

Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-3-oxopropanoate (i) tert-Butyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-3-oxopropanoate

The subtitle compound was prepared by the method of example 10 using 3-tert-butoxy-3-oxopropanoic acid. Yield 100 mg.

MS: APCI (+ve): 585 (M+1).

(ii) Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-3-oxopropanoate

The product from step (i) (100 mg) was dissolved in methanol (3 ml) and 4N—HCl in dioxane added. The mixture was stirred at rt for 5 h and purified by RPHPLC, which afforded the title compound. Yield 80 mg

¹H NMR δ (DMSO-d₆) 9.68 (1H, s), 7.23 (1H, m), 7.13 (1H, m), 7.06 (2H, m), 6.11 (2H, brs), 4.51 (2H, s), 4.16 (2H, t), 3.65 (2H, t), 3.60 (6H, s), 3.27 (2H, t), 3.00 (2H, s), 2.99 (2H, m), 1.85-1.98 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 0.91 (3H, t).

MS: APCI (+ve): 543 (M+1).

EXAMPLE 21

Methyl[3-({acetyl[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate

The product from example 20 step (i) (100 mg) was dissolved in DCM (1 ml) and TFA (0.2 ml) added. The mixture was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO₃and dried. The mixture was purified by RPHPLC, which afforded the title compound. Yield 30 mg

¹H NMR δ (DMSO-d₆) 7.01-7.29 (4H, m), 6.12 (2H, brs), 4.50 (2H, s), 4.15 (2H, t), 3.65 (2H, t), 3.61 (2H, s), 3.60 (3H, s), 3.26 (2H, t), 2.00 (3H, s), 1.83-1.99 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 0.91 (3H, t).

MS: APCI (+ve): 485 (M+1).

EXAMPLE 22

Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](methylsulfonyl)amino]methyl}phenyl)acetate

The title compound was prepared by the method of example 17 using product example 9 step (iii) (100 mg) and methanesulfonic anhydride (76 mg).

yield 60 mg.

¹H NMR δ (DMSO-d₆) 7.33-7.49 (4H, m), 6.33 (2H, brs), 4.53 (2H, s), 4.38 (2H, t), 3.84 (2H, s), 3.82 (2H, m), 3.82 (3H, s), 3.37 (2H, t), 3.12 (3H, s), 2.10 (2H, m), 1.86 (2H m), 1.62 (2H, m), 1.14 (3H, t).

MS: APCI (+ve): 521 (M+1).

EXAMPLE 23

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)[2R]-propyl]-(pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

The product of example 1, step (ix) (300 mg) and pyrrolidine-1,2-dicarboxylic acid 1-(R)-tert-butyl ester (146 mg) were dissolved in DCM (10 ml) and HATU (258 mg) added. After 1 h, more HATU (258 mg) and (R)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (146 mg) were added to the mixture. The mixture was stirred at rt for 16 h and TFA (5 ml) added and stirred for 4 h. The reaction mixture was concentrated in vacuo to dryness then redissolved in methanol before being purified by RPHPLC, to give the title compound. Yield 19 mg.

¹H NMR δ (DMSO-d₆) 8.19 (1H, s), 7.27-7.03 (5H, m), 6.46 (2H, d, J=14.9 Hz), 4.71-4.49 (2H, m), 4.41 (1H, d), 4.20-4.04 (4H, m), 3.71-3.60 (4H, m), 3.47-3.33 (2H, m), 3.34-3.26 (2H, m), 3.26-3.18 (2H, m), 3.17-3.07 (2H, m), 2.92-2.81 (1H, m), 2.19-2.02 (2H, m), 2.02-1.86 (2H, m), 1.82-1.69 (2H, m), 1.69-1.56 (2H, m), 1.45-1.32 (2H, m), 0.94-0.88 (3H, m).

MS: APCI (+ve): 540 (M+1).

EXAMPLE 24

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S,4R](4-hydroxy-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

The product of example 1, step (ix) (0.27 g) was dissolved in DCM (10 ml) and treated with (R)-4-triethylsilanyloxy-pyrrolidine-1,2-dicarboxylic acid 1-(S)-tert-butyl ester (211 mg) and HATU (232 mg). The reaction was stirred at rt for 16 h and TFA (2 ml) added and stirred for 4 h. The reaction mixture was concentrated to dryness in vacuo puffed by RPHPLC to give the title compound. Yield 114 mg.

¹H NMR δ (DMSO-d₆) 8.22 (1H, s), 7.28-7.02 (4H, m), 6.46 (2H, d), 4.61 (1H, s), 4.60-4.36 (1H, m), 4.27-4.19 (2H, m), 4.17-4.06 (3H, m), 3.70-3.61 (4H, m), 3.34-3.23 (2H, m), 3.19-3.06 (2H, m), 2.00-1.86 (2H, m), 1.87-1.73 (2H, m), 1.70-1.56 (2H, m), 1.44-1.31 (2H, m), 0.96-0.84 (3H, m).

MS: APCI (+ve): 556 (M+1).

EXAMPLE 25

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S]-(1-methyl-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

The product of example 1, step (ix) (0.43 g), 1-methyl-pyrrolidine-2-carboxylic acid (0.13 g) and HATU (0.37 g) were stirred in DCM (5 ml) at rt for 7 days. The reaction mixture was purified by SCX and RPHPLC, to give the title compound. Yield 24 mg.

¹H NMR δ (DMSO-d₆) 9.92 (1H, d), 9.61 (1H, s), 7.30-7.03 (5H, m), 6.44 (2H, s), 4.67-4.56 (2H, m), 4.54-4.42 (2H, m), 4.15-4.05 (4H, m), 3.69-3.58 (4H, m), 2.84-2.73 (4H, m), 2.05 (3H, s), 2.10-1.97 (2H, m), 1.97-1.84 (2H, m), 1.86-1.73 (2H, m), 1.66-1.53 (2H, m), 1.37-1.24 (2H, m), 0.96-0.83 (3H, m).

MS: APCI (+ve): 554 (M+1).

EXAMPLE 26

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(3-piperazin-1-yl-propionyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

The product of example 1, step (ix) (0.27 g) was dissolved in DCM (10 ml) and treated with 4-(2-carboxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.16 g) and HATU (0.23 g). The reaction was stirred at rt for 16 h, before 2 mls of TFA added. The mixture was purified by RPHPLC, to give the title compound. Yield 3 mg.

¹H NMR δ (DMSO-d₆) 9.93 (1H, d), 7.27-7.06 (4H, m), 6.52-6.41 (2H, m), 4.60 (1H, s), 4.48 (1H, s), 4.13 (2H, s), 3.71-3.59 (4H, m), 3.61 (3H, s), 3.43-3.16 (10H, m), 2.87-2.75 (2H, m), 2.02-1.91 (2H, m), 1.91-1.80 (2H, m), 1.68-1.58 (2H, m), 1.42-1.31 (2H, m), 0.91 (3H, t).

MS: APCI (+ve): 583 (M+1).

The compounds of Examples 27 to 103 were prepared by processes analogous to Example 1, step (x) using commercially available amines.


Example
Number	Molecule IUPAC Name	M + 1

27	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[3-	694
	(1-piperidyl)propyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
28	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[3-	667
	(diethylcarbamoyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate
29	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	644
	phenyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate
30	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-	680
	oxo-2-pyrrolidin-1-yl-ethyl)piperazin-1-
	yl]acetyl]amino]methyl]phenyl]acetate
31	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1-	568
	piperidyl)acetyl]amino]methyl]phenyl]acetate
32	ethyl 4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	641
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]piperazine-1-
	carboxylate
33	2-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	611
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(2-
	cyanoethyl)amino]acetic acid
34	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(benzyl-	661
	(2-dimethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate
35	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	611
	carbamoyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate
36	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-	570
	hydroxypyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
37	tert-butyl (2S)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	654
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-
	carboxylate
38	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2-	637
	cyanoethyl-(oxolan-2-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate
39	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-	619
	(pyridin-4-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate
40	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	597
	ethylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
41	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-	619
	(2-pyridin-4-ylethyl)amino)acetyl]amino]methyl]phenyl]acetate
42	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	637
	pyrrolidin-1-yl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate
43	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-	597
	carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
44	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,6-	566
	dihydro-2H-pyridin-1-yl)acetyl]amino]methyl]phenyl]acetate
45	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-	572
	(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate
46	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-	626
	(cyclohexyl-(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate
47	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-	598
	(hydroxymethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate
48	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-	612
	aminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
49	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-	612
	hydroxyethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate
50	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[methyl-	611
	(1-methyl-4-piperidyl)amino]acetyl]amino]methyl]phenyl]acetate
51	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	674
	benzyl-4-hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate
52	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	685
	cinnamylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
53	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[2-	657
	(2-hydroxyethoxy)ethyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
54	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3-	599
	dimethylaminopropyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate
55	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-	599
	(dimethylcarbamoylmethyl-methyl-
	amino)acetyl]amino]methyl]phenyl]acetate
56	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-	597
	carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
57	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-	598
	[(2S,6R)-2,6-dimethylmorpholin-4-yl]acetyl]amino]methyl]phenyl]acetate
58	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	597
	methyl-1,4-diazepan-1-yl)acetyl]amino]methyl]phenyl]acetate
59	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-	570
	morpholin-4-ylacetyl)amino]methyl]phenyl]acetate
60	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-	661
	hydroxyphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
61	methyl 2-[4-[[[2-[3-(acetyl-methyl-amino)pyrrolidin-1-yl]acetyl]-[3-(6-	625
	amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl]amino]methyl]phenyl]acetate
62	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3S)-3-	597
	dimethylaminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
63	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	646
	pyridin-4-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
64	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-	654
	dimethylaminopropyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
65	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	611
	propan-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
66	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-	654
	(dimethylcarbamoylmethyl)piperazin-1-
	yl]acetyl]amino]methyl]phenyl]acetate
67	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2-	634
	hydroxy-2-phenyl-ethyl)-methyl-
	amino]acetyl]amino]methyl]phenyl]acetate
68	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-	597
	(aminomethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate
69	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-	571
	(2-methylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate
70	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-	586
	thiomorpholin-4-ylacetyl)amino]methyl]phenyl]acetate
71	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	645
	phenylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
72	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1,3-	602
	dihydroisoindol-2-yl)acetyl]amino]methyl]phenyl]acetate
73	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-	569
	piperazin-1-ylacetyl)amino]methyl]phenyl]acetate
74	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(1-	651
	piperidyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate
75	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	646
	pyridin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
76	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	584
	hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate
77	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(4-	663
	fluorophenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
78	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	582
	methyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate
79	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2,5-	552
	dihydropyrrol-1-yl)acetyl]amino]methyl]phenyl]acetate
80	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	702
	benzothiazol-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
81	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-	654
	(ethoxycarbonylmethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate
82	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-	640
	dimethylaminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
83	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-	659
	methylphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
84	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	661
	ethylsulfonylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
85	(2S,4R)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	614
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]-4-hydroxy-
	pyrrolidine-2-carboxylic acid
86	(2S)-2-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	662
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-methyl-amino]-
	3-phenyl-propanoic acid
87	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-	584
	(hydroxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
88	3-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	690
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(1,1-
	dioxothiolan-3-yl)amino]propanoic acid
89	3-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	654
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-cyclohexyl-
	amino]propanoic acid
90	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-	599
	(2-ethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate
91	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-	613
	(3-ethylaminopropyl)amino)acetyl]amino]methyl]phenyl]acetate
92	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,4-	616
	dihydro-1H-isoquinolin-2-yl)acetyl]amino]methyl]phenyl]acetate
93	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-	637
	(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
94	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[(1-	680
	methyl-4-piperidyl)methyl]piperazin-1-
	yl]acetyl]amino]methyl]phenyl]acetate
95	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-	552
	prop-2-ynyl-amino)acetyl]amino]methyl]phenyl]acetate
96	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(1-	701
	methyl-4-piperidyl)-phenethyl-amino]acetyl]amino]methyl]phenyl]acetate
97	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-	653
	(oxolan-2-ylmethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate
98	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-	569
	aminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
99	tert-butyl (2R)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-	654
	(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-
	carboxylate
100	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-	647
	pyrimidin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
101	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-	554
	pyrrolidin-1-ylacetyl)amino]methyl]phenyl]acetate
102	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-	598
	(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate
103	methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-	598
	(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate

Biological Assay

Human TLR7 Assay

Recombinant human TLR7 was stably expressed in a HEK293 cell line already stably expressing the pNiFty2-SEAP reporter plasmid; integration of the reporter gene was maintained by selection with the antibiotic zeocin. The most common variant sequence of human TLR7 (represented by the EMBL sequence AF240467) was cloned into the mammalian cell expression vector pUNO and transfected into this reporter cell-line. Transfectants with stable expression were selected using the antibiotic blasticidin. In this reporter cell-line, expression of secreted alkaline phosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promoter comprising five NFkB sites combined with the proximal ELAM-1 promoter. TLR signaling leads to the translocation of NFkB and activation of the promoter results in expression of the SEAP gene. TLR7-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37° C. with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the log of the minimal effective concentration of compound to induce SEAP release (pMEC). For example

Compounds of Examples: 1, 4, 7 and 18 have pMEC>7.7

Claims

The invention claimed is:

1. A compound of formula (I)

wherein

R¹represents hydrogen, hydroxyl, or a C₁-C₆alkoxy, C₂-C₅alkoxycarbonyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₆-C₁₀aryl, C₅-C₁₀heteroaryl or C₃-C₈cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, a C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₅alkoxycarbonyl, amino (NH₂), (mono)-C₁-C₆alkylamino and (di)-C₁-C₆alkylamino group;

Y¹represents a single bond or C₁-C₆alkylene;

X¹represents a single bond, an oxygen, sulphur atom, sulphonyl (SO₂) or NR³;

Z¹represents a C₂-C₆alkylene or C₃-C₈cycloalkylene group, each group being optionally substituted by at least one hydroxyl;

X²represents NR⁴;

Y²represents a single bond or C₁-C₆alkylene;

Y³represents a single bond or C₁-C₆alkylene;

n is an integer 0, 1 or 2;

R represents halogen or a C₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆hydroxyalkoxy, C₁-C₆haloalkoxy, amino (NH₂), (mono)-C₁-C₆alkylamino, (di)-C₁-C₆alkylamino group or a C₃-C₈saturated heterocyclic ring containing a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₂-C₅alkylcarbonyl and C₂-C₅alkoxycarbonyl;

R²represents hydrogen or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C₁-C₆alkoxy, a C₂-C₁₀acyloxy, group selected from a C₂-₅alkylcarbonyloxy group, a C₂-C₅alkenylcarbonyloxy group, a C₂-C₅alkynylcarbonyloxy group, a C₆-C₉arylcarbonyloxy group and a C₅-C₉heteroarylcarbonyloxy group, each of which acyloxy groups may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C₁-C₃alkoxy and phenyl providing that the total number of carbon atoms in the acyloxy group does not exceed 10, amino (NH₂), (mono)-C₁-C₆alkylamino, (di)-C₁-C₆alkylamino group and a C₃-C₈saturated heterocyclic ring containing a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring in turn being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, C₂-C₅alkylcarbonyl and C₂-C₅alkoxycarbonyl group;

R³represents hydrogen or C₁-C₆alkyl;

R⁴represents CO₂R⁵, SO₂R⁵, COR⁵, SO₂NR⁶R⁷and CONR⁶R⁷;

R⁵independently represents

(i) 3- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms selected from a ring group NR⁸, S(O)_mor oxygen, the 3- to 8-membered heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C₁-C₆alkyl and C₁-C₆alkoxy group, or

(ii) a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, C₁-C₆alkyl, C₁-C₃haloalkyl, carboxyl, S(O)_mR⁹, OR¹⁰, CO₂R¹⁰, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹, NR¹⁰COR⁹, or

(iii) a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, CN, C₃-C₈cycloalkyl, S(O)_pR¹², OR¹³, COR¹³, CO₂R¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR¹³R¹⁴, NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², NR¹³SO₂R¹²or a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group or a heterocyclic ring, the latter three groups may be optionally substituted by one or more substituents independently selected from C₁-C₆alkyl (optionally substituted by hydroxy, C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, amino, C₁-C₆alkylamino, di-C₁-C₆alkylamino, NH₂C(O)—, C₁-C₆alkylNHC(O), di-C₁-C₆alkyl NC(O), —OCH₂CH₂OH, pyrrolidinyl, pyrrolidinylcarbonyl, furanyl, piperidyl, methylpiperidyl or phenyl), C₂-C₆alkenyl (optionally substituted by phenyl), halogen, hydroxy, cyano, carboxy, amino, C₁-C₆alkylamino, di-C₁-C₆alkylamino, NH₂C(O)—, C₁-C₆alkyl NHC(O)—,di-C₁-C₆alkyl NC(O), C₁-C₆alkoxycarbonyl, C₁-C₆alkylsulphonyl, C₁-C₆alkylcarbonylamino, C₁-C₆alkylcarbonylmethylamino, phenyl (optionally substituted by hydroxy, fluoro or methyl), pyrrolidinyl, pyridyl, piperidinyl, benzothiazolyl or pyrimidinyl;

R⁶represents hydrogen or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl group or heterocyclic ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, OR¹⁵, S(O)_qR¹⁵, CO₂R¹⁶, COR¹⁶, NR¹⁶R¹⁷, CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶CO₂R¹⁵, SO₂NR¹⁶R¹⁷, NR¹⁶SO₂R¹⁵, or a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group or heterocyclic ring, the latter three groups being optionally substituted by one or more substituents independently selected from, C₁-C₆alkyl, C₃-C₈cycloalkyl, halogen, S(O)_qR¹⁵, CO₂R¹⁶, COR¹⁶, hydroxy or cyano; and

R⁷represents hydrogen, a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₈cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, C₃-C₈cycloalkyl, a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group, carboxy, cyano, OR¹⁵, hydroxy or NR¹⁸R¹⁹, or

R⁶and R⁷together with the nitrogen atom to which they are attached fowl a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)_mor oxygen, the heterocyclic ring, may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, carboxyl, cyano, OR²⁰, NR²¹R²², S(O)_qR²³, COR²⁴, CO₂R²⁴, NR²⁴R²⁵, CONR²⁴R²⁵, NR²⁴COR²⁵, NR²⁴CO₂R²³, SO₂NR²⁴R²⁵, NR²⁴SO₂R²³, C₆-C₁₀aryl , C₅-C₁₀heteroaryl group, heterocyclic ring, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl or C₃-C₈cycloalkyl group, the latter seven groups being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, OR²⁰, S(O)_qR²³, COR²⁴, CO₂R²⁴, NR²⁴R²⁵, CONR²⁴R²⁵, NR²⁴CO₂R²³, NR²⁴COR²⁵, SO₂NR²⁴R²⁵, NR²⁴SO₂R²³, a heterocyclic ring or a C₆-C₁₀aryl or C₅-C₁₀heteroaryl group, the latter three groups being optionally substituted by one or more substituents independently selected from C₁-C₆alkyl, halogen, hydroxy or cyano;

R⁸represents hydrogen, CO₂R²⁶, COR²⁶, SO₂R²⁶, C₁-C₆alkyl or C₃-C₆cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, and NR²⁷R²⁸;

R¹⁰, R¹¹, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²⁶, R²⁷or R²⁸each independently represents hydrogen, and a C₁-C₆alkyl or C₃-C₆cycloalkyl group;

R²⁴and R²⁵each independently represents hydrogen, and a C₁-C₆alkyl or C₃-C₆cycloalkyl group; or

R²⁴and R²⁵together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)_mor oxygen;

R⁹, R¹², R¹⁵and R²³represent C₁-C₆alkyl or C₃-C₆cycloalkyl;

R¹³and R¹⁴are defined as for R⁶and R⁷respectively;

R²⁰represents a C₁-C₆alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl or OR²³;

m, p, q and r each independently represent an integer 0, 1 or 2; and

A represents a C₆-C₁₀aryl or C₅-C₁₂heteroaryl group;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein X¹represents oxygen.

3. The compound according to claim 1, wherein Y¹represents C₁-C₆alkylene and R¹represents hydrogen.

4. The compound according to claim 1, wherein Z¹represents C₂-C₆alkylene.

5. The compound according to claim 1, wherein Y²represents C₁-C₆alkylene.

6. The compound according to claim 1 wherein A represents C₆-C₁₀aryl.

7. The compound according to claim 1 wherein Y³represents C₁-C₆alkylene.

8. The compound according to claim 1 wherein R²represents C₁-C₆alkyl.

9. The compound according to claim 1 wherein R⁴represents SO₂R⁵.

10. The compound according to claim 1 wherein R⁴represents COR⁵.

11. A compound selected from:

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(4-methylpiperazin-1-yl)acetyl]amino}methyl)phenyl]acetate,

Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethylglycyl)amino]methyl}phenyl)acetate,

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][4-(dimethylamino)butanoyl]amino}methyl)phenyl]acetate,

Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethyl-□-alanyl)amino]methyl}phenyl)acetate,

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N,N-bis(2-hydroxyethyl)glycyl]amino}methyl)phenyl]acetate,

Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate,

Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(methylsulfonyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate,

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,

Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](glycyl)amino]methyl}phenyl)acetate,

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylthio)acetyl]amino}methyl)phenyl]acetate,

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfinyl)acetyl]amino}methyl)phenyl]acetate,

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfonyl)acetyl]amino}methyl)phenyl]acetate,

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylthio)propanoyl]amino}methyl)phenyl]acetate,

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylsulfonyl)propanoyl]amino}methyl)phenyl]acetate,

Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N-(methylsulfonyl)glycyl]amino}methyl)phenyl]acetate,

tert-Butyl 4-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoate,

4-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoic acid,

Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-3-oxopropanoate,

Methyl[3-({acetyl[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate,

Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](methylsulfonyl)amino]methyl}phenyl)acetate,

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)[2R]-propyl]-(pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S,4R](4-hydroxy-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S]-(1-methyl-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,

(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(3-piperazin-1-yl-propionyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[3-(1-piperidyl)propyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[3-(diethylcarbamoyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1-piperidyl)acetyl]amino]methyl]phenyl]acetate,

Ethyl 4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]piperazine-1-carboxylate,

2-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(2-cyanoethyl)amino]acetic acid,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(benzyl-(2-dimethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-carbamoyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-hydroxypyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

tert-Butyl (2S)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2-cyanoethyl-(oxolan-2-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(pyridin-4-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2-pyridin-4-ylethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrrolidin-1-yl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,6-dihydro-2H-pyridin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(cyclohexyl-(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(hydroxymethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-aminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-hydroxyethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[methyl-(1-methyl-4-piperidyl)amino]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzyl-4-hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-cinnamylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3-dimethylaminopropyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(dimethylcarbamoylmethyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-1,4-diazepan-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-morpholin-4-ylacetyl)amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-hydroxyphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[[2-[3-(acetyl-methyl-amino)pyrrolidin-1-yl]acetyl]-[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3S)-3-dimethylaminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-4-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-dimethylaminopropyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-propan-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(dimethylcarbamoylmethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2-hydroxy-2-phenyl-ethyl)-methyl-amino]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(aminomethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2-methylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-thiomorpholin-4-ylacetyl)amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1,3-dihydroisoindol-2-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-piperazin-1-yl)acetyl)amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(1-piperidyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(4-fluorophenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2,5-dihydropyrrol-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzothiazol-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(ethoxycarbonylmethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-dimethylaminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-methylphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylsulfonylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

(2S,4R)-1-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl]-4-hydroxy-pyrrolidine-2-carboxylic acid,

(2S)-2-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl-methyl-amino]-3-phenyl-propanoic acid,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl-(1,1-dioxothiolan-3-yl)amino]propanoic acid,

3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl-cyclohexyl-amino]propanoic acid,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(2-ethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(3-ethylaminopropyl)amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,4-dihydro-1H-isoquinolin-2-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[(1-methyl-4-piperidyl)methyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-prop-2-ynyl-amino)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(1-methyl-4-piperidyl)-phenethyl-amino]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(oxolan-2-ylmethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-aminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

tert-Butyl (2R)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrimidin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-pyrrolidin-1-ylacetyl)amino]methyl]phenyl]acetate,

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate, and

Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,

and pharmaceutically acceptable salts thereof.

12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 11 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. A process for the preparation of a pharmaceutical composition as claimed in claim 12 which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed claim 1 or claim 11 with a pharmaceutically acceptable adjuvant, diluent or carrier.

14. A combination of a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and one or more agents independently selected from:

a non-steroidal glucocorticoid receptor agonist;

a selective β₂adrenoceptor agonist;

a phosphodiesterase inhibitor;

a protease inhibitor;

a glucocorticoid;

an anticholinergic agent; and

a modulator of chemokine receptor function selected from antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-C family.